The alpha-1 subunit of the Na+,K+-ATPase (ATP1A1) is required for macropinocytic entry of respiratory syncytial virus (RSV) in human respiratory epithelial cells

PLoS Pathogens
Matthias LingemannShirin Munir

Abstract

Human respiratory syncytial virus (RSV) is the leading viral cause of acute pediatric lower respiratory tract infections worldwide, with no available vaccine or effective antiviral drug. To gain insight into virus-host interactions, we performed a genome-wide siRNA screen. The expression of over 20,000 cellular genes was individually knocked down in human airway epithelial A549 cells, followed by infection with RSV expressing green fluorescent protein (GFP). Knockdown of expression of the cellular ATP1A1 protein, which is the major subunit of the Na+,K+-ATPase of the plasma membrane, had one of the strongest inhibitory effects on GFP expression and viral titer. Inhibition was not observed for vesicular stomatitis virus, indicating that it was RSV-specific rather than a general effect. ATP1A1 formed clusters in the plasma membrane very early following RSV infection, which was independent of replication but dependent on the attachment glycoprotein G. RSV also triggered activation of ATP1A1, resulting in signaling by c-Src-kinase activity that transactivated epidermal growth factor receptor (EGFR) by Tyr845 phosphorylation. ATP1A1 signaling and activation of both c-Src and EGFR were found to be required for efficient RSV uptake. S...Continue Reading

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Citations

Dec 29, 2020·Frontiers in Immunology·Sandra Axberg PålssonAnna-Lena Spetz
Dec 23, 2020·Nature Microbiology·Nora SchmidtMathias Munschauer
Mar 4, 2021·American Journal of Physiology. Lung Cellular and Molecular Physiology·Derek B McMahonRobert J Lee
Oct 31, 2020·Pharmacology & Therapeutics·Farah ElawarDavid J Marchant
May 4, 2021·Frontiers in Pharmacology·Kauê Francisco Corrêa Souza E SouzaCassiano Felippe Gonçalves-de-Albuquerque
May 22, 2021·Frontiers in Pharmacology·Xinlei Li, Tao Peng

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Datasets Mentioned

BETA
KT992094

Methods Mentioned

BETA
transfection
Assay
ELISA
flow cytometry
confocal microscopy
X-ray
co-immunoprecipitation
pull-down
PCR

Software Mentioned

Leica Application Suite X ( LAS - X )
Leica LAS - X
Studio
ImageJ
Huygens Essential deconvolution
ImageXpress
ImageQuant TL
Image
MetaXpress
Imaris

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